Pharmaceutical aerosol composition containing HFA 227 and HFA 134a

ABSTRACT

In a solution composition for use in an aerosol inhaler which comprises an active material, a propellant containing a hydrofluoroalkane, a cosolvent and optionally a low volatility m compound the use of a mixture of HFA 134a and HFA 227 allows to modulate the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler to target specific regions of the respiratory tract. Moreover the fine particle dose (FPD) of the active ingredient in the composition increases by reducing the metering chamber volume.

[0001] The invention relates to aerosol compositions for pharmaceuticaluse. In particular, this invention relates to aerosol compositions foruse in pressurised metered dose inhalers (MDIs). The invention alsorelates to solution aerosol compositions, wherein the propellantcomprises HFA 134a or HFA 227 or their mixtures.

[0002] Another aspect of the invention relates to pressurised MDIs fordispensing said compositions.

[0003] Inhalers are well known devices for administering pharmaceuticalproducts to the respiratory tract by inhalation.

[0004] Active materials commonly delivered by inhalation includebronchodilators such as β2 agonists and anticholinergics,corticosteroids, anti-leukotrienes, anti-allergics and other materialsthat may be efficiently administered by inhalation, thus increasing thetherapeutic index and reducing side effects of the active material.

[0005] There are a number of types of inhaler currently available. Themost widely used type is a pressurised metered dose inhaler (MDI) whichuses a propellant to expel droplets containing the pharmaceuticalproduct to the respiratory tract as an aerosol. Formulations used inMDIs (aerosol formulations) generally comprise the active material, oneor more liquefied propellants and a surfactant or a solvent.

[0006] For many years the preferred propellants used in aerosols forpharmaceutical use have been a group of chlorofluorocarbons which arecommonly called Freons or CFCs, such as CCl₃F (Freon 11 or CFC-11),CCl₂F₂ (Freon 12 or CFC-12), and CClF₂-CClF₂ (Freon 114 or CFC-114).Chlorofluorocarbons have properties particularly suitable for use inaerosols, including high vapour pressure which generates clouds ofdroplets of a suitable particle size from the inhaler.

[0007] Recently, the chlorofluorocarbon (CFC) propellants such as Freon11 and Freon 12 have been implicated in the destruction of the ozonelayer and their production is being phased out.

[0008] Hydrofluoroalkanes [(HFAs) known also as hydro-fluoro-carbons(HFCs)] contain no chlorine and are considered less destructive to ozoneand these are proposed as substitutes for CFCs.

[0009] HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to bethe best candidates for non-CFC propellants and a number of medicinalaerosol formulations using such HFA propellant systems are disclosed inseveral patent applications.

[0010] Many of these applications, in which. HFAs are used aspropellant, propose the addition of one or more of adjuvants includingcompounds acting as cosolvents, surface active agents includingfluorinated and non-fluorinated surfactants, dispersing agents includingalkylpolyethoxylates and stabilizers.

[0011] Cosolvents which may be used in these formulations includealcohols such as ethanol and polyols such as propylene glycol.

[0012] Medicinal aerosol formulations using such propellant systems aredisclosed in, for example, EP 0372777. EP 0372777 requires the use ofHFA 134a as a propellant in combination with both a surfactant and anadjuvant having higher polarity than the propellant.

[0013] For aerosol suspension compositions, a surfactant is often addedto improve the physical stability of the suspension. EP 0372777 statesthat the presence of surfactant assists in the preparation of stable,homogeneous suspensions and may also assist in the preparation of stablesolution formulations.

[0014] Surfactants also lubricate the valve components in the inhalerdevice.

[0015] The use of propylene glycol as a solvent having a higher polaritythan the propellant in HFA pressurised metered dose inhalersformulations has been mentioned in several other patent applications andfor example in:

[0016] EP 504112 relates to a pharmaceutical aerosol formulation freefrom CFCs containing a propellant (hydrocarbon, HFA or a mixture), oneor more pharmaceutical active ingredients, a non-ionic surfactant andoptionally other conventional pharmaceutical auxiliaries suitable foraerosol formulations comprising solvents having a higher polarity thanthe propellant, other non-ionic surfactants as valve lubricants,vegetable oils, phospholipids, taste masking agents.

[0017] DE 4123663 describes a medical aerosol composition containing adispersion or suspension of an active agent in association with acompound with surface-active or lipophilic properties,heptafluoropropane as propellant and an alcohol such as ethanol and/orpropylene glycol.

[0018] Other applications propose the addition of dispersing agents tothe composition. U.S. Pat. No. 5,502,076 concerns compositions used ininhalation aerosols comprising an HFA, leukotriene antagonists anddispersing agent comprising 3C-linked triesters, vitamin E acetate,glycerin, t-BuOH, or transesterified oil/polyethylene glycol.

[0019] EP 384371, describes a propellant for an aerosol, comprisingpressure-liquefied HFA 227 in a mixture with pressure-liquefied propaneand/or n-butane and/or iso-butane and/or dimethyl ether and/or1,1-difluoroethane. The document also discloses foam formulations(shaving and shower foams) containing glycerol as additive.

[0020] The effectiveness of an aerosol device, for example an MDI, is afunction of the dose deposited at the appropriate site in the lungs.Deposition is affected by several parameters, of which the mostimportant are the Fine Particle Dose (FPD) and the aerodynamic particlesize. Solid particles and/or droplets in an aerosol formulation can becharacterized by their mass median aerodynamic diameter (MMAD, thediameter around which the mass aerodynamic diameters are distributedequally).

[0021] The FPD gives a direct measure of the mass of particles within aspecified size range and is closely related to the efficacy of theproduct.

[0022] Particle deposition in the lung depends largely upon threephysical mechanisms: (1) impaction, a function of particle inertia; (2)sedimentation due to gravity; and (3) diffusion resulting from Brownianmotion of fine, submicrometer (<1 μm) particles. The mass of theparticles determines which of the three main mechanisms predominates.

[0023] The effective aerodynamic diameter is a function of the size,shape and density of the particles and will affect the magnitude offorces acting on them. For example, while inertial and gravitationaleffects increase with increasing particle size and particle density, thedisplacements produced by diffusion decrease. In practice, diffusionplays little part in deposition from pharmaceutical aerosols. Impactionand sedimentation can be assessed from a measurement of the mass medianaerodynamic diameter (MMAD) which determines the displacement acrossstreamlines under the influence of inertia and gravity, respectively.

[0024] Aerosol particles of equivalent MMAD and GSD (Geometric StandardDeviation) have similar deposition in the lung irrespective of theircomposition. The GSD is a measure of the variability of the aerodynamicparticle diameters.

[0025] For inhalation therapy there is a preference for aerosols inwhich the particles for inhalation have a diameter of about 0.8 to 5 μm.Particles which are larger than 5 μm in diameter are primarily depositedby inertial impaction in the oropharynx, particles 0.5 to 5 μm indiameter, influenced mainly by gravity, are ideal for deposition in theconducting airways, and particles 0.5 to 3 μm in diameter are desirablefor aerosol delivery to the lung periphery. Particles smaller than 0.5μm may be exhaled.

[0026] Respirable particles are generally considered to be those withaerodynamic diameters less than 5 μm. These particles, particularlythose with a diameter of about 3 μm, are efficiently deposited in thelower respiratory tract by sedimentation.

[0027] Besides the therapeutic purposes, the size of aerosol particlesis important in respect to the side effects of the drugs. For example,it is well known that the oropharynx deposition of aerosol formulationsof steroids can result in side effects such as candidiasis of mouth andthroat.

[0028] On the other hand a higher systemic exposure to the aerosolparticles due to deep lung penetration can enhance the undesiredsystemic effects of the drugs. For example, the systemic exposure tosteroids can produce side effects on bone metabolism and growth.

[0029] It has been reported that the particle size characteristics ofHFA aerosol formulations of the state of the art are often verydifferent from the products to be replaced.

[0030] HFA substitutes may not be pharmaceutically or clinicallyequivalent and adjustment of dose and regimen may be necessary, givingproblems for doctor, pharmacist and patient.

[0031] An alternative is the seamless transition from the old to the newformulas which demands the same deposition of the drug in the lung. Forany product, this can be inferred from the amount of drug and itsparticle size distribution in the aerosol cloud. Matching CFC and HFAformulations with suspension technology is practicable because theparticle size of the aerosol cloud is dominated by the particle size ofthe suspended drug, defined by the milling or precipitation process.

[0032] However, when, as commonly occurs, solution formulations areunavoidable, the volumetric contribution of suspended particles isabsent and much finer clouds, largely defined by the concentration ofthe drug in the solution, are generated. In these circumstances, aco-solvent, such as alcohol, is often added to ensure satisfactorysolubility. The fine clouds from such formulations give more extensivedeposition in the lung periphery than their CFC counterparts.

[0033] EP 0553298 describes an aerosol formulation comprising: atherapeutically effective amount of beclomethasone 17,21 dipropionate(BDP); a propellant comprising a hydrofluorocarbon selected from thegroup consisting of HFA 134a, HFA 227, and a mixture thereof, andethanol in an amount effective to solubilize the beclomethasone 17,21dipropionate in the propellant. The formulation is further characterizedin that substantially all of the beclomethasone 17,21 dipropionate isdissolved in the formulation and that the formulation contains no morethan 0,0005% by weight of any surfactant.

[0034] It has been reported in literature that these new formulations ofbeclomethasone dipropionate (BDP) as a solution in HFA 134a deliver aparticle size distribution with a MMAD of 1.1 μm. This means that theperipheral pulmonary deposition of very small particles increases andsubmicronic particles can easily be directly absorbed from the alveoliinto the bloodstream. The rate and extent of systemic absorption issignificantly increased and as a consequence undesired effects forexample certain side effects can increase. A relatively large fractionof the dose is exhaled. The implications of this for clinical efficacyand toxic effects are great. They arise because the principles offormulation using HFAs may modify the physical form of the respiredcloud.

[0035] It has now been surprisingly found that in solution formulationsof the present application comprising an active material, a propellantcontaining a hydrofluoroalkane (HFA), a cosolvent and optionally a lowvolatility compound, the use of a mixture of HFA 134a and of HFA 227allows the modulation of the MMAD of the aerosol particles on actuationof the inhaler to a value which is suited for the pulmonaryadministration.

[0036] Mixtures of hydrofluoroalkanes have been previously used insuspension-based pMDI compositions to vary the density of the continuousphase in order to match the density of the suspended drug and maximizethe physical stability of the pMDI suspension.

[0037] Williams R. O. et al. in Drug Dev. Ind. Pharm. 24(8), 763-770,1998 investigated the influence of propellant composition on thecharacteristics of suspension aerosol compositions. The results showedthat as the density of the propellant blends approached the density ofthe suspended drug particles, the formulation became more physicallystable.

[0038] Analogously, WO93/11747 discloses that in suspension aerosolcompositions the density of the propellant may be changed by using HFA134a and HFA 227 mixtures so as to bring it to approximately the samevalue of the density of the active ingredient, minimizing thereby thesedimentation of the drug particles.

[0039] Therefore the aerosol compositions using the new propellantsystems disclosed in the known prior art seek to overcome problems ofphysical stability of the formulations.

[0040] It has surprisingly been found that in solution compositions byusing a mixture of HFA 134a and HFA 227 and optionally a low volatilitycomponent, the MMAD of the aerosol particles on actuation of the inhalercan be modulated and thus the compositions may be formulated so that theaerodynamic particle size characteristics are optimized.

[0041] Advantageously, the low volatility component has a vapourpressure at 25° C. not more than 0.1 kPa, preferably not more than 0.05kPa.

[0042] The low vapour pressure of the low volatility component is to becontrasted with that of the cosolvent which preferably has a vapourpressure at 25° C. not less than 3 kPa, more preferably not less than 5kPa.

[0043] The cosolvent has advantageously a higher polarity than that ofthe propellant and the cosolvent is used to increase the solubility ofthe active material in the propellant.

[0044] Advantageously the cosolvent is an alcohol. The cosolvent ispreferably ethanol. The cosolvent may include one or more materials.

[0045] The low volatility component may be a single material or amixture of two or more materials.

[0046] In general terms the low volatility component can be anycompound, safe and compatible with the propellant system of theinvention capable to influence either the size or the density of theaerosol particle so affecting the MMAD.

[0047] We have found that glycols are particularly suitable for use asthe low volatility component, especially propylene glycol, polyethyleneglycol and glycerol.

[0048] Other particularly suitable materials are thought to includeother alcohols and glycols, for example alkanols such as decanol (decylalcohol), sugar alcohols including sorbitol, mannitol, lactitol andmaltitol, glycofural (tetrahydro-furfurylalcohol) and dipropyleneglycol.

[0049] The low volatility component may include esters for exampleascorbyl palmitate and tocopherol. Among the esters isopropyl myristateis particularly preferred.

[0050] It is also envisaged that various other materials may be suitablefor use as the low volatility component including vegetable oils,organic acids for example saturated carboxylic acids including lauricacid, myristic acid and stearic acid; unsaturated carboxylic acidsincluding sorbic acid, and especially oleic acid, which has beenpreviously used in aerosol formulations, in order to improve thephysical stability of drug suspensions, as a dispersing agent useful inkeeping the suspended particles from agglomerating; saccharine, ascorbicacid, cyclamic acid, amino acids or aspartame; alkanes for exampledodecane and octadecane; terpenes for example menthol, eucalyptol,limonene; sugars for example lactose, glucose, sucrose; polysaccharidesfor example ethyl cellulose, dextran; antioxidants for example butylatedhydroxytoluene, butylated hydroxyanisole; polymeric materials forexample polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrollidone;amines for example ethanolamine, diethanolamine, triethanolamine;steroids for example cholesterol, cholesterol esters.

[0051] The amount of low volatility component in the composition dependsto some extent upon its density and the amount of active material andcosolvent in the composition. Advantageously, the composition includesnot more than 20% by weight of the low volatility component. Preferablythe composition includes not more than 10% by weight of the lowvolatility component.

[0052] On actuation of the inhaler, the propellant and the ethanolvaporise but because of the low vapour pressure of the low volatilitycomponent, that component generally will not.

[0053] It is thought that it is preferable for the composition tocontain at least 0.2%, preferably at least 1% by weight of the lowvolatility component. The composition may contain between 1% and 2% byweight.

[0054] According to the present invention, as it can be noticed from theresults reported in the tables, the influence on the MMAD of theparticles is correlated to the ratio of the two HFA components (as wellas to the amount and density of the low volatility component).

[0055] The MMAD can be modulated by changing the ratio between HFA 134aand HFA 227; said ratio may range from 10:90 to 90:10.

[0056] From the data reported in Table 1, it is clear that MMAD isincreased by increasing the proportion of HFA 227 in the mixture.

[0057] Most advantageously, the composition is such that, on actuationof the aerosol inhaler in use, the MMAD of the aerosol particles is notless than 21m. For some active materials the MMAD is preferably not lessthan 2.5 μm and for a few formulations, the preferred MMAD will begreater than 3 μm or even greater than 4 μm.

[0058] In some cases a small quantity of water may be added to thecomposition to improve the solution of the active material and/or thelow volatility component in the cosolvent.

[0059] The active material may be one or more of any biologically activematerial which could be administered by inhalation. Active materialscommonly administered in that way include β2 agonists, for examplesalbutamol and its salts, steroids for example beclomethasonedipropionate or anti-cholinergics for example ipratropium bromide andcombinations thereof.

[0060] As indicated above, on actuation of the inhaler, the aerosolparticles advantageously have an MMAD of not less than 2 μm, for manyformulations more preferably not less than 2.5 μm.

[0061] It has also been found, and it is a further object of theinvention, that it is possible to increase the “fine particle dose” orFPD of the active ingredients in the compositions of the invention,without affecting MMAD, by decreasing the metering chamber volume of themetered dose inhaler (increasing thereby the space above it named“sump”) and/or changing the ratio between the metering chamber and thespace above by increasing the sump. In particular, by reducing themetering chamber volume from 50 μl to 25 μl at sump volume constant, itis possible to increase the fine particle delivery up to 40%.

[0062] This result could be only obtained with solution compositions inwhich the MMAD of the particles is higher than 2 μm and it isparticularly surprising since it is known from Williams R. O. et al. inPharmaceutical Research 14(4), 438-443, 1997 that in suspension basedPMDI containing HFA 134a the aerodynamic particle size distribution wasnot influenced as the metering chamber volume of the valve wasincreased.

[0063] The solution formulations with MMAD>2 may be obtained by using ametering chamber <40 μl, preferably 25 μl: the fine particle delivery(Stage 3 to filter; <4.7 μm) determined through a Andersen CascadeImpactor is increased by at least 10% in comparison with the sameformulation packaged with a valve with a metering chamber of at least 50μl and the same sump, as it will be shown hereinbelow.

[0064] Using a reduced metering chamber volume (e.g. about 40 μl orlower for a conventional inhaler), favourable results are obtained evenwith aerosol compositions wherein the propellant consists either in HFA227 or in HFA 134a alone.

[0065] Also provided is a method of filling an aerosol inhaler with acomposition, the method comprising filling the following components intothe inhaler

[0066] (a) one or more active materials,

[0067] (b) optionally one or more low volatility components,

[0068] (c) one or more cosolvents

[0069] followed by the addition of a propellant containing ahydrofluoroalkane (HFA) or a mixture of HFAs.

[0070] Embodiments of the invention will now be described by way ofexample.

[0071] The aerosol compositions of the invention described below wereprepared by the following method. The required components of acomposition were added into a can in the following order: drug,non-volatile additive, absolute ethanol. After crimping of the valve onto the can, the propellant was added through the valve. The weight gainof the can after each component was added was recorded to allow thepercentage, by weight, of each component in the formulation to becalculated.

[0072] The aerodynamic particle size distribution of each formulationwas characterized using a Multistage Cascade Impactor according to theprocedure described in the European Pharmacopoeia 2nd edition, 1995,part V.5.9.1. pages 15-17. In this specific case an Andersen CascadeImpactor (ACI) was used. Results represented were obtained from tencumulative actuations of a formulation. Deposition of the drug on eachACI plate was determined by high pressure liquid chromatography. Themass median aerodynamic diameter (MMAD) and geometric standard deviation(GSD) were calculated from plots of the cumulative percentage undersizeof drug collected on each ACI plate (probit scale), against the uppercut off diameter for each respective ACI plate (log10 scale). The fineparticle dose of each formulation was determined from the mass of drugcollected on Stages 3 through to Filter (<4.7 μm) divided by the numberof actuations per experiment.

[0073] Table 1 shows the MMAD characteristics of aerosol formulationscontaining beclomethasone dipropionate (BDP) (active material), glycerolas low volatility component and different mixtures of HFA 134a and HFA227. As can be seen, the MMAD is substantially influenced by the ratioof the two fluorocarbons whereas FPD is substantially unaffected.

[0074] The presence of the low volatility component contributes to themodulation of the MMAD: its percent content (w/w) can be properlyadapted to obtain the desired MMAD.

[0075] Table 2 shows the effects of valve chamber (also known asmetering chamber) volumes at sump volume constant on the generation ofaerosol clouds.

[0076] In particular, the data shown in Table 2 show that FPD increaseswith decreasing valve chamber volume and that FPD can be increased bymore that 40% by reducing the volume of a valve metering chamber. MMADor GSD are not conversely affected by changing the volume of thevalve-metering chamber.

[0077] Therefore, the compositions of the invention consisting ofaerosol drug solution in a mixture of 134a and 227 HFA propellants, acosolvent and optionally a low volatility component, added into anaerosol inhaler having a chamber volume ranging from 25 to 50 μl,constitute a delivery system which allow improvement of the deliverycharacteristics of drugs to the lung by modulating the aerodynamicparticle size and size distribution so that the pattern of depositiongives the desired clinical effect.

[0078] To obviate possible chemical stability problems of activeingredients in solution in HFA propellants metered-dose inhalers havingpart or all of their internal metallic surfaces consisting of stainlesssteel, anodized aluminium or lined with an inert organic coating can beemployed. TABLE 1 Effect of HFA 134a/HFA 227 mixtures upon the MMAD ofpMDI solution formulation BDP 250 μg/shot Ethanol 15% (w/w) Glycerol1.3% (w/w) HFA to 12 ml Actuator = 0.30 mm HFA 227/ MMAD FPD FPD₃ < 4.7μm* HFA 134a (μm) (%) (μg) 100:0  4.2, 3.9, 3.8 20, 20, 24 47, 45, 5075:25 3.7, 3.7 25, 25 56, 57 50:50 3.4, 3.7 25, 25 56, 56 25:75 3.3, 3.227, 28 60, 62  0:100 2.8, 2.8 27, 27 58, 59

[0079] TABLE 2 Effect of Valve Chamber Volume upon the FPD of pMDIscontaining HFA 134a and HFA 227 Solutions Formulations BDP 50 μg/shotEthanol 13% (w/w) Glycerol 1.3% (w/w) HFA to 12 ml Chamber MeteredVolume FPD < 4.7 μm MMAD Dose (μl) Propellant (μg) (μm) GSD (μg)actuator orifice 0.30 mm 25 HFA 134a 19.2 2.6 2.0 57 50 13.9 2.8 2.1 49100 11.7 2.7 2.2 51 25 HFA 227 16.4 3.6 2.1 58 50 13.1 3.5 2.2 51 10012.6 3.5 2.2 49 actuator orifice 0.25 mm 25 HFA 134a 26.0 2.8 1.9 55

1. A composition in form of solution for use in an aerosol inhaler, thecomposition comprising an active material, a propellant containing ahydrofluoroalkane (HFA), a cosolvent, optionally a low volatilitycomponent characterized in that the propellant consists of a mixture ofHFA 227 and HFA 134a.
 2. A composition according to claim 1, wherein theratio of HFA 227/HFA 134a ranges from 10:90 to 90:10.
 3. A compositionaccording to claim 1 or 2, wherein the low volatility component has avapour pressure at 25° C. lower than 0.1 kPa.
 4. A composition accordingto claim 3, wherein the low volatility component has a vapour pressureat 25° C. lower than 0.05 kPa.
 5. A composition according to anypreceding claim, wherein the cosolvent has' a vapour pressure at 25° C.lower than 3 kPa.
 6. A composition according to any preceding claim,wherein the cosolvent has a vapour pressure at 25° C. lower than 5 kPa.7. A composition according to any preceding claim, wherein the cosolventis an alcohol.
 8. A composition according to any preceding claim,wherein the low volatility component includes a glycol, oleic acid orisopropyl myristate.
 9. A composition according to any preceding claim,wherein the composition includes not more than 20% by weight of the lowvolatility component.
 10. A composition according to any precedingclaim, wherein the composition includes at least 0.2% by weight of thelow volatility component.
 11. A composition according to any precedingclaim, the composition being such that, on actuation of the aerosolinhaler in use, the MMAD of the aerosol particles is not less than 2 μm.12. An aerosol inhaler containing a solution composition comprising anactive material, a propellant containing one or more hydrofluoroalkane,a cosolvent and optionally a low volatility component wherein theparticle MMAD is greater than 2 μm and the fine particle dose (<4.7 μm)is >30%.
 13. An aerosol inhaler according to claim 12 wherein theparticle MMAD is greater than 2 μm and the fine particle dose (<4.7 μm)is >40%.
 14. An aerosol inhaler according to claims 12 and 13 whereinthe particle MMAD is greater than 0.2 μm and the fine particle dose.(<4.7 μm) is >50%.
 15. An aerosol inhaler according to claims 12 to 14having a chamber volume ranging from 25 to 50 μl yielding an increase ofFPD compared to inhalers having chamber volumes larger than 50 μl. 16.An aerosol inhaler according to claims 12 to 15 containing thecompositions of claims 1-11.
 17. An aerosol inhaler according to claims12 to 16 having part or all of the internal surfaces consisting ofstainless steel, anodised aluminium or lined with an inert organiccoating.
 18. A delivery system for the administration of drugs to thelung consisting of aerosol drug solution in a mixture of 134a and 227HFA propellants, a cosolvent and optionally a low volatility component,in an aerosol inhaler having a chamber volume ranging from 25 to 50 μl.